This project proposes to establish a collaboration of investigators involved in lymphedema treatment and human genetics in order to identify genetically informative families affected with lymphedema. These families would provide DNA for linkage studies to define potential loci and ultimately the gene(s) involved in the pathogenesis of inherited lymphedema. The investigators would constitute a core study group with the potential to be enlarged for future studies in genotype-phenotype correlation focused on treatment of lymphedema in genetically characterized individuals. Lymphedema is a chronic disabling condition which results in swelling of the extremities either as the result of impaired lymphatic flow or overproduction of lymph. Over 250 million individuals may suffer from various forms of lymphedema worldwide. Patients with lymphedema suffer from recurrent local infections, are unable to move about normally, are socially stigmatized and may be at increased risk for developing cancers such as lymphangiosarcoma. This is an incurable disorder requiring lifelong attention. Despite a general understanding of the pathophysiology resulting in the development of lymphedema, essentially nothing is known about the genes which regulate the development of the lymphatic system and gene products which mediate the physiology of lymph flow. There have been no previously reported attempts to map the gene(s) for these disorders except early attempts at linkage to blood groups, despite the attractive prior reports of large dominant families with various forms of inherited lymphedema. No candidate genes have been put forward for study. Since the treatments which exist for lymphedema are rarely based on controlled trials, understanding the genetic basis for the subset of inherited lymphedemas would be a major advance in classification of these disorders and would serve as a basis for the evaluation of careful treatment trials addressing genotype-phenotype correlation.